DESCRIPTION: The cAMP Response Element Binding Protein (CREB) has been shown t be a critical molecule involved in the formation of protein synthesis-dependen long-term memory (LTM) in a number of experimental systems. they are intereste in the molecular mechanisms which occur during the consolidation process. Th goal of their research is to understand the molecular processes which underl the behavioral requirements for LTM formation in Drosophila, repetition o training trials and rest intervals between each trial. The underlyin assumption is that differential activation of signal transduction pathway occurs during training, and that the convergence point for these differen pathways is the CREB molecule. Ultimately the decision whether to proceed o not with de novo protein synthesis and LTM formation, is determined by CREB perhaps by the ratio of activities of activator to blocker isoforms. Specifically, the applicants propose to ask if a number of alternative isoform of the fly CREB gene function as blockers of LTM, if phosphorylation of certai blocking forms affect their activities, and if phosphorylation affects th activity of an activator isoform. Utilizing CREB-responsive transcription, the also propose to identify the cells which are involved in LTM formation facilitating future molecular analysis of mechanisms, identification o "downstream" target genes of activated CREB, and detailed physiologica analysis of LTM formation. Because of the underlying behavioral and molecular conservation in the process of LTM formation, these studies provide a starting point for analysis of human learning and memory formation. Detailed molecular information about the role of CREB in LTM formation may lead to molecular mechanisms causing certain human cognitive dysfunctions, diagnostic tools, pharmaceutical reagents and therapies. They may also point the way towards therapeutic solutions for degenerative diseases of normal and abnormal aging.